1. Field
The following embodiments relate to inhibitors of biting insects and more particularly to compositions and methods for reducing the incidence of insect bites. Even more particularly, the disclosed compositions and methods inhibit biting insects, for example mosquitoes, from biting a subject after landing on a subject. In some embodiments, such inhibitors may also be used, for example, to reduce swelling, inflammation and/or itching after an insect bite. In various embodiments, the compositions may be administered orally to inhibit insects from biting subjects.
2. Background
Multiple species of flying and crawling insects, including mosquitoes, ticks, flies, midges, chiggers, and fleas, bite subjects, such as human subjects. Although such insects are mostly a nuisance in North America, they transmit more than 100 bacterial, protozoan, parasitic, and rickettsial diseases to humans worldwide.
Mosquitoes transmit more diseases to humans than any other biting insect. Mosquitoes are the vectors responsible for transmitting several forms of viral encephalitis, yellow fever, dengue fever, bancroftian filariasis, and epidemic polyarthritis to humans; more than 700,000,000 people are infected yearly. Malaria, which is transmitted by the bite of a mosquito infected with the single-cell protozoan Plasmodium, is responsible for 3,000,000 deaths annually (Fradin MS: Mosquitoes and mosquito repellents: a clinician's guide. Ann Intern Med Jun. 1, 1998 ; 128(11): 931–40).
There are over 2500 different species of mosquitoes throughout the world, of which 150 species occur in the United States. A single female mosquito can lay over 200 eggs at a time. Mosquito eggs can survive for more than five years. All mosquitoes need water to complete their life cycle. Not all species bite humans; some prefer birds, others prefer horses, and some will even bite frogs and turtles. Only females take blood; males feed only on plant nectar. Mosquitoes can fly considerable distances; some species remain close to their larval habitats while others can fly 20 miles or more. Mosquitoes do not develop in grass or shrubbery, although adults frequently rest in these areas during daylight hours. Mosquitoes are responsible for more human deaths than any other living creature.
West Nile Virus (WNV) is a flavivirus belonging taxonomically to the Japanese encephalitis serocomplex that includes the closely related St. Louis encephalitis (SLE) virus, Kunjin and Murray Valley encephalitis viruses, as well as others. WNV was first isolated in the West Nile Province of Uganda in 1937. The first recorded epidemics occurred in Israel during 1951–1954 and in 1957. Epidemics have been reported in Europe in the Rhone delta of France in 1962 and in Romania in 1996. The largest recorded epidemic occurred in South Africa in 1974.
An outbreak of arboviral encephalitis in New York City and neighboring counties in New York state in late August and September 1999, was subsequently confirmed as caused by West Nile virus, based on the identification of virus in human, avian, and mosquito samples.
Although it is not known when and how West Nile virus was introduced into North America, international travel of infected persons to New York or transport by imported infected birds may have played a role. WNV can infect a wide range of vertebrates; in humans it usually produces either asymptomatic infection or mild febrile disease, but can cause severe and fatal infection in a small percentage of patients. Within its normal geographic distribution of Africa, the Middle East, western Asia, and Europe, WNV has not been documented to cause epizootics in birds. Crows and other birds with antibodies to WNV are common, suggesting that asymptomatic or mild infection usually occurs among birds in those regions. Similarly, substantial bird virulence of SLE virus has not been reported. Therefore, an epizootic producing high mortality in crows and other bird species is unusual for either WNV or SLE virus. For both viruses, migratory birds may play an important role in the natural transmission cycles and spread. Like SLE virus, WNV is transmitted principally by Culex species mosquitoes, but also can be transmitted by Aedes, Anopheles, and other species. The predominance of urban Culex pipiens mosquitoes trapped during this outbreak suggests an important role for this species. By August 2002, the WNV, carried by mosquitoes, had spread to 41 states, causing a total of 24 fatalities.
Infected ticks can transmit Lyme disease, Rocky Mountain spotted fever, ehrlichiosis, babesiosis, tularemia, and tick paralysis. Flies are the vectors responsible for transmitting other diseases such as African trypanosomiasis, leishmaniasis, onchocerciasis, and loiasis to humans. Fleabites may transmit plague, and, in South America, kissing bugs transmit Chagas disease.
Despite the need for an effective oral inhibitor of biting insects, no such agent has been identified thus far. Ingested garlic, brewer's yeast, and thiamine are not effective at inhibiting insects from biting. The quest to develop the perfect topical insect repellent has been an ongoing scientific goal for years but has yet to be achieved.
The ideal insect inhibitor and/or repellent would provide protection from multiple species of biting arthropods; remain effective for at least 8 hours; cause no irritation to the skin or mucous membranes; exhibit no systemic toxicity; be resistant to abrasion and wash-off; and be greaseless and odorless, i.e., cosmetically appealing.
A distinction is made herein between insect repellents, which prevent biting insects from landing on a subject, and inhibitors of biting insects, which inhibit insects from biting a subject after landing. Although a particular composition may have efficacy as both an inhibitor and a repellant of biting insects, commercially available formulations typically act as insect repellants. Commercial insect repellents may generally be characterized as involving topical application, usually are effective for limited duration, may cause severe irritation of skin or mucous membranes, may be abraded or washed off, possess a pungent odor and greasy texture, and arguably may have toxic side effects.
To be effective, an insect repellent should be volatile enough to maintain an effective vapor concentration at the skin surface, but it must not evaporate so rapidly that it quickly loses its effectiveness. Multiple factors play a role in effectiveness, including the concentration, frequency, and uniformity of application; the user's activity level and overall attractiveness to blood-sucking arthropods; and the number and species of potentially biting insects. The effectiveness of any insect repellent is reduced by abrasion from clothing; evaporation and absorption from the skin surface; wash-off from sweat, rain, or water; a windy environment; and high ambient temperatures. Each 10° C. increase in temperature may lead to as much as a 50% reduction in protection time. (www.emedicine.com/derm/topics540.htm)
Commercial insect repellents do not cloak the user in a chemical veil of protection. Any untreated exposed skin may be readily bitten by insects. Protection from both the nuisance and the health risks associated with insect bites is presently achieved by avoiding infested habitats, wearing protective clothing, and applying an insect repellent. As discussed below, such methods are unsatisfactory for a variety of reasons.
Current Insect Repellants
DEET
Currently marketed insect repellents fall into 2 categories: manufactured (chemical) repellents and natural (plant-derived) repellents. In general, the chemical repellents have a broader spectrum of efficacy and a greater duration of action than botanical repellents.
Commercial products include OFF!™, Cutter, Repel™, Sawyer™, Ben's™ (all in multiple formulations), and Ultrathon™. Registered for use by the general public since 1957, N, N-diethyl-3-methylbenzamide (previously called N, N-diethyl-m-toluamide), or DEET, remains the standard of currently available insect repellents. DEET, a broad-spectrum repellent, is effective against many species of crawling and flying insects, including mosquitoes, biting flies, midges, chiggers, fleas, and ticks.
The Environmental Protection Agency (EPA) estimates that about 30% of the US population uses a DEET-based product every year. Worldwide use exceeds 200 million people annually. Empirical testing of more than 20,000 other compounds over the last 45 years has not led to a more effective insect repellent than DEET being brought to market.
In the United States, DEET is sold in concentrations ranging from 5–40% and 100%. DEET is available in multiple formulations, including solutions, lotions, creams, gels, aerosol and pump sprays, and impregnated towelettes. EPA regulations require that the concentration of DEET in each product be disclosed on its label.
The 3M Company manufactures a polymer-based 33% DEET cream, called Ultrathon™, which is the standard issue repellent given to the US military. When tested under multiple environmental and climatic field conditions, Ultrathon™ was as effective as 75% DEET, providing up to 12 hours of greater than 95% protection against mosquito bites. Sawyer Products makes a controlled-release 20% DEET lotion, which traps the chemical in a protein particle that slowly releases it to the skin surface. This formulation provides a repellency equivalent to a standard 50% DEET preparation, lasting about 5 hours. Products with 5–35% DEET provide adequate protection under most conditions. However, the American Academy of Pediatrics recommends that DEET-containing repellents used on children should not contain more than 10% DEET. In addition, DEET containing insect repellants exhibit most of the drawbacks of chemical insect repellants discussed above.
Young children should not apply DEET-containing repellents themselves, to minimize the possibility of irritation of eyes or mucous membranes. Inadvertent exposure of such tissues to higher concentrations of DEET may result in pain, watering of the eyes, and general tissue irritation. For the same reasons, DEET should not be applied to a child's hands. To prevent irritation after the repellent is applied, it should be wiped from the palm surfaces to prevent inadvertent contact with the eyes, mouth, and genitals. The repellents should never be used on cuts, wounds, and inflamed, irritated, or eczematous skin. Aerosol formulations should not be inhaled or sprayed into the eyes. Contact with plastics (e.g., watch crystals, eyeglass frames), rayon, spandex, and painted or varnished surfaces should be avoided because DEET can damage those surfaces. Once indoors, the repellent-treated areas should be washed with soap and water. Washing the repellent from the skin surface is particularly important under circumstances where a repellent is likely to be applied for several consecutive days.
Repellents containing DEET must be carefully applied because they can damage plastics (such as watch crystals and eyeglasses frames), rayon, spandex, other synthetic fabrics, leather, and painted or varnished surfaces. DEET does not damage natural fibers, such as cotton or wool, and has no effect on nylon. There are many accounts of the unpleasant odor or greasy feel of DEET.
In children, concentrations greater than 10% of DEET, too frequent applications, and oral ingestion are associated with toxicity, including encephalopathy and seizures. Deaths have been documented in relation to improper exposure to DEET. DEET is not recommended for infants less than two month of age.
IR3535
IR3535 (3-[N-butyl-N-acetyl]-aminopropionic acid) is a chemical repellent that has been available in Europe for 20 years and has been sold in the United States since 1999. This repellent (at 7.5%) is currently available through the Avon Corporation as Skin-So-Soft Bug Guard Plus IR3535. IR3535 is structurally similar to the amino acid alanine, and the EPA classifies it as a biopesticide. It is labeled for use against mosquitoes, ticks, and biting flies. In a recent laboratory comparative study of the efficacy of insect repellents to prevent mosquito bites, Avon Corporation's IR3535-based repellent provided an average complete protection time of only about 23 minutes (range, 10–60 min) (Fradin, 2002).
Piperidine
Although not yet for sale in the United States, a piperidine-based repellent is sold in Europe as Autan Bayrepel. Derived from pepper, this repellent is labeled for use against ticks, mosquitoes, and flies. The manufacturer claims DEET-like efficacy against mosquitoes, lasting as few as 2 hr and sometimes as long as 8 hours, depending on the species.
Skin-So-Soft Bath Oil
Avon Corporation's Skin-So-Soft bath oil received considerable media attention several years ago when some consumers reported it to be effective as a mosquito repellent. Studies have shown that Skin-So-Soft bath oil has a minimal repellent effect, and it is at least 10 times less effective than 12.5% DEET. The limited mosquito repellent effect of Skin-So-Soft oil may be due to its fragrance or to other components of its formulation, which may possess some repellent activity. The manufacturer has never marketed the bath oil as an insect repellent.
Thousands of plants have been tested as sources of insect repellents. Although none of the plant-derived chemicals tested to date demonstrate the broad effectiveness and duration of the protection of DEET, a few appear to show repellent activity.
Citronella
Marketed products containing citronella include Natrapel™, Buzz Away™, Herbal Armor™, and Green Ban™. Oil of citronella is a plant-derived ingredient found in many natural or herbal insect repellents marketed in the United States. Oil of citronella is extracted from the grass plants Cymbopogon nardus and Cymbopogon winterianus. Conflicting data exist on the efficacy of citronella-based products. This data variation may be attributed to differences in study methodology, location, and species of the biting insects tested. One comparative laboratory study demonstrated that marketed citronella-based insect repellents protected against mosquito bites for an average of less than 20 minutes. In general, citronella-based repellents provide considerably shorter protection than DEET repellents. Therefore, they require more frequent reapplication to maintain their effectiveness. For maximum repellent effectiveness of these products, it is recommended to repeat applications at one-hour intervals.
Soybean Oil
This repellent may provide longer-lasting protection than citronella-based repellents. In some studies, one soybean oil product provided complete protection against mosquito bites for as long as 3.5 hours, and against blackflies for as long as 10 hours. However, the benefits of soybean oil as an insect repellent have not been extensively documented.
Eucalyptus
A derivative, p-menthane-3,8-diol (PMD), isolated from the oil of the lemon eucalyptus plant has shown promise as an insect repellent. A 30% PMD preparation appears to provide protection comparable to 20% DEET but requires more frequent reapplication to maintain the same level of protection. PMD-based repellents show low toxicity, but care must be taken to keep them out of the eyes because PMD can cause significant eye irritation.
A search for the perfect topical insect repellent has continued. The ideal agent would remain effective for at least 8 hours and have no toxic side effects. No available topical insect repellent meets those criteria.
There remains a need for an oral inhibitor of biting insects that would fulfill all of the criteria listed in Paragraph 0011 above. Such an agent would inhibit multiple species of biting arthropods, including but not limited to mosquitoes, remain effective for at least 8 hours, cause no irritation to the skin or mucous membranes, cause no systemic toxicity especially in children, be resistant to being rubbed or washed off and not have an unpleasant taste or smell.